Thrombosis and thrombosis-related complications are under-recognized, yet contribute important morbidity and mortality for children with congenital heart disease. Patients with functional single ventricle undergoing palliative staging procedures towards eventual Fontan procedure are at particularly high risk, with 40% having clinically important thrombosis events before reaching superior cavopulmonary connection (SCPC), and a further 28% having events up to Fontan. The use of thromboprophylaxis is limited by lack of a sufficient evidence base and suboptimal risk-benefit ratio of currently used agents. An innovative 2 step randomized double blind clinical trial utilizing new agents is proposed to rigorously address this significant problem. For Step 1, subjects with functional single ventricle who are expected to proceed to SCPC will be enrolled at the time of initial presentation and diagnosis, and randomized to prasugrel or dabigatrin after baseline thrombophilia and genetics assessment. Subjects will be monitored up to SCPC for the primary outcome of clinically important thrombosis events, as well as compliance and bleeding complications. For Step 2, remaining subjects will have their assigned study drug discontinued just before SCPC, and after SCPC will be randomized to prasugrel or dabigatran. Surveillance vascular ultrasound will be obtained 4-10 days after SCPC, and subjects will be followed to 18 months of age with monitoring for the primary outcome, compliance and bleeding complications. At 18 months of age, surveillance vascular ultrasound and neurodevelopmental assessment will be obtained. Competing risks methodology will be used for data analysis to determine relative hazard reduction for time-related clinically important thrombosis events both for Step 1 and Step 2. The study will have 85% power to detect a 25% and 33% relative risk reduction for Step 1 and Step 2, respectively. Risk (bleeding)/benefit (thrombosis prevention) ratios will be also be compared. Factors (thrombophilia, genetic polymorphisms) associated with thrombosis and risk/benefit will be explored. This study will be an important contribution to the evidence base, study the use of novel agents in a high risk population, and identify factors that will enable risk-stratification and improved outcomes. RELEVANCE: Patients with functional single ventricle (severe congenital heart disease), continue to have the highest rates of morbidity and mortality, and thrombosis is an important contributor that has not been adequately recognized or addressed. The proposed research will rigorously determine the risk and spectrum of thrombosis, test new agents for preventing thrombosis, and identify thrombophilia and genetic polymorphism factors that may lead to better targeting of interventions and overall improved outcomes.